Chronic fatigue syndrome (CFS) has a genetic component that contributes up to 38% of the risk, but this risk is yet to be linked to specific genes. Many CFS patients have problems with chronic viral infections. The PIs propose that allelic variances in antibody receptor genes contribute to the vulnerability of CFS patients to chronic viruses. When viral infections become chronic, the K-cell subset of natural killer (NK) cells recognizes antibodies to viral proteins and kills infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Impaired ADCC is consistent with the immunopathology of CFS: patients have difficulties controlling EBV, H. simplex I&II, HHV-6 and HCMV chronic viral infections. Fc-IgG receptors (FcRs) enable K-cells to recognize antibodies bound to cells and to kill infected cells. Allelic polymorphisms of FcRs impair ADCC. K cells express two activating FcRs, CD16A & CD32C, and sometimes an inhibitory FcR, CD32B. Drs. Hudig and Barao hypothesize that CFS patients have lower ADCC than healthy individuals due to genetic variations of CD16A, CD32C and CD32B and that particular alleles are significant disease-determining factors in familial CFS. Phenotypic variations of expression of FcRs and other proteins may also lower the patients' ADCC. The PIs have extensive experience with lymphocyte cytotoxicity and their collaborator, Daniel L. Peterson, MD, is a world-renowned CFS clinician. Aim 1: To determine if FcR genotypes that impair ADCC are risk factors for CFS. The main receptor CD16A has 2 alleles, 158V that is optimal and 158F that is less effective for ADCC. Another receptor CD32C also has ORF and stop alleles; the latter encodes no CD32C and creates an impaired phenotype. Chromosomal deletion of CD32C causes inhibitory CD32B expression by K-cells. The PIs will: a) determine the allelic polymorphisms of CFS patients vs. healthy family members and unrelated controls; b) evaluate 'impairing' alleles with CFS severity; and c) examine families with 2 to 4 relatives with CFS for inheritance of CD16A F/F, CD32Cstop/stop or CD32Cdel with disease. If so, these alleles are candidate risk factors for CFS. S.K. Anderson, Ph.D., NCI, is collaborating for the genetic characterizations. Aim 2: To determine if FcR cell phenotype(s) and low ADCC are risk factors for CFS. The number of K-cells in blood and the frequency of K-cells among NKs vary widely. Cellular densities of CD16A and CD32C also will affect ADCC. The PIs will: a) determine the numbers, frequencies and MFIs of K-cells for CD16A, CD32C and CD32B by flow cytometry; b) measure ADCC by 51Cr assays and CD107a. They expect that CFS patients will have low ADCC that correlates with CD16A F/F, CD32C stop/stop and CD32Cdel. Innovation: The PIs will determine for the first time a specific genetic contribution to familial CFS. New elements of the project include: 1) FcR allelic polymorphisms; 2) phenotypes of K-cells in CFS; and 3) the ADCC of CFS patients. Clinical significance: This study will identify subsets of CFS patients who may benefit from ADCC-enhancing therapies, e.g., MMT 6 & ADAM17 inhibitors and anti-CD137 co-stimulation.